N714K
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialAsparagine → Lysine at position 714 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications. AlphaMissense 0.992 (near-maximum), DynaMut2 ΔΔG -0.44 kcal/mol (destabilising). The FOURTH Atlas variant at position 714 (with N714T, N714S, and D771H in the same network).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | I712 | Gained |
| Hydrogen bond | A716 | — | Lost |
| Hydrogen bond | E717 | E717 | Preserved |
| Hydrogen bond | S718 | S718 | Preserved |
| Hydrogen bond | I767 | — | Lost |
| Hydrogen bond | D771 | — | Lost |
| Polar contact | — | I712 | Gained |
| Polar contact | A716 | — | Lost |
| Polar contact | E717 | E717 | Preserved |
| Polar contact | S718 | S718 | Preserved |
| Polar contact | I767 | — | Lost |
| Polar contact | D771 | D771 | Preserved |
| Van der Waals | — | I712 | Gained |
| Van der Waals | A716 | — | Lost |
| Van der Waals | E717 | — | Lost |
| Van der Waals | — | S718 | Gained |
| Hydrophobic | — | I712 | Gained |
| Hydrophobic | E717 | E717 | Preserved |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Conflicting classifications of pathogenicity, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 714 same neighbor environment as N714T/N714S: SER715 (2.4 Å), ASP713 (2.5 Å), PHE770 (4.4 Å), ALA716 (4.4 Å), ASP771 (4.7 Å).
Replacing N714 with lysine introduces a positive charge into the D713-D771 polar network — adjacent to two existing negative charges. The K714 amine likely forms salt bridges with D713 and/or D771, restructuring the polar network entirely (where the wild-type N714 amide H-bonded but did not carry charge).
The |ΔΔG| of 0.44 reflects fold accommodation. AlphaMissense's 0.992 (near-maximum) confirms severe functional consequence — the charge introduction disrupts the wild-type partner-recognition geometry.
Druggability Assessment
Mechanism is charge introduction into the D713-D771 polar network. Therapeutic strategy: same microregion as N714T, N714S, D771H.
Why this matters
Feed this card to Wolfram Intelligence
Download the N714K PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.